title: Aging and sleep deprivation induce the unfolded protein response in the pancreas: implications for metabolism.
abstract: Sleep disruption has detrimental effects on glucose metabolism through pathways that remain poorly defined. Although numerous studies have examined the consequences of sleep deprivation (SD) in the brain, few have directly tested its effects on peripheral organs. We examined several tissues in mice for induction of the unfolded protein response (UPR) following acute SD. In young animals, we found a robust induction of BiP in the pancreas, indicating an active UPR. At baseline, pancreata from aged animals exhibited a marked increase in a pro-apoptotic transcription factor, CHOP, that was amplified by SD, whereas BiP induction was not observed, suggesting a maladaptive response to cellular stress with age. Acute SD increased plasma glucose levels in both young and old animals. However, this change was not overtly related to stress in the pancreatic beta cells, as plasma insulin levels were not lower following acute SD. Accordingly, animals subjected to acute SD remained tolerant to a glucose challenge. In a chronic SD experiment, young mice were found to be sensitized to insulin and have improved glycemic control, whereas aged animals became hyperglycemic and failed to maintain appropriate plasma insulin concentrations. Our results show that both age and SD cooperate to induce the UPR in pancreatic tissue. While changes in insulin secretion are unlikely to play a major role in the acute effects of SD, CHOP induction in pancreatic tissues suggests that chronic SD may contribute to the loss or dysfunction of endocrine cells and that these effects may be exacerbated by normal aging.
authors.affiliation: Division of Sleep Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Nirinjini
authors.initials: N
authors.lastname: Naidoo
authors.forename: James G
authors.initials: JG
authors.lastname: Davis
authors.forename: Jingxu
authors.initials: J
authors.lastname: Zhu
authors.forename: Maya
authors.initials: M
authors.lastname: Yabumoto
authors.forename: Kristan
authors.initials: K
authors.lastname: Singletary
authors.forename: Marishka
authors.initials: M
authors.lastname: Brown
authors.forename: Raymond
authors.initials: R
authors.lastname: Galante
authors.forename: Beamon
authors.initials: B
authors.lastname: Agarwal
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Baur
mesh_terms: D000375:Aging / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002490:Central Nervous System / Q000473:pathology; D003345:Corticosterone / Q000097:blood; D005502:Food; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology*; D012892:Sleep Deprivation / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D056811:Unfolded Protein Response
chemical_list: D001786:Blood Glucose; D007328:Insulin; D003345:Corticosterone
keywords: aging; behavior; glucose tolerance; mouse; sleep deprivation